Transplantation therapy for human diabetes is limited by a shortage of donor organs, and outcomes are complicated by immunosuppression. While porcine pancreas is a candidate for organ donation, the severity of humoral rejection effectively precludes the use of pigs as whole pancreas donors in non-human primates or humans. Isolated islets of Langerhans (islets), like most other cell transplants, can be transplanted into non-human primates or humans without initiating humoral rejection. But sustained insulin independence from, for example, pig to primate islet or neonatal islet transplantation, can be achieved only through the use of immune-suppressive agents that are not approved for human use or would result in an unacceptable level of morbidity in humans (see e.g., Hering et al. 2006 Nature Medicine 12, 301-303; Cardona et al. 2006 Nature Medicine 12: 304-306; Schroeder 2003 Journal of Surgical Research 111, 109-119).
Xenotransplantation in host mesentery of pig pancreatic primordia obtained very early during organogenesis (e.g., embryonic day 28 (E28)) can obviate the need for immune-suppression in rat or rhesus macaques (see Rogers et al. 2004 Am. J. Physiol. 286, E502-E509; Rogers et al. 2005 Transplant Immunology 14: 67-75; Rogers et al. 2006 Transplant Immunology 16, 176-184; Rogers and Hammerman 2008 Organogenesis 4, 48-51; Rogers et al. 2007 Xenotransplantation 14, 591-602). Glucose tolerance can be normalized in streptozotocin (STZ)-diabetic (type 1) Lewis rats or ZDF (type 2) diabetic rats via transplantation in mesentery of pig pancreatic primordia obtained very early during embryogenesis (on embryonic day 28 (E28)—just after the organ differentiates and prior to the time dorsal and ventral anlagen fuse) without host immune-suppression (see Rogers et al. 2004 Am. J. Physiol. 286, E502-E509; Rogers et al. 2005 Transplant Immunology 14: 67-75; Rogers et al. 2006 Transplant Immunology 16, 176-184; Rogers and Hammerman 2008 Organogenesis 4, 48-51). No rat insulin was reported to be detected in STZ-treated rats. Rather porcine insulin circulates post-transplantation of E28 pig pancreatic primordia (embryonic pancreas) and levels increase after an oral glucose load (Rogers et al. 2005 Transplant Immunology 14: 67-75; Rogers et al. 2006 Transplant Immunology 16, 176-184). Cells expressing insulin and porcine proinsulin mRNA with beta cell morphology are reported to engraft in host mesentery, mesenteric lymph nodes, liver and pancreas post-transplantation (Rogers et al. 2005 Transplant Immunology 14: 67-75; Rogers et al. 2006 Transplant Immunology 16, 176-184; Rogers and Hammerman 2008 Organogenesis 4, 48-51). Cells originating from E28 pig pancreatic primordia are reported to engraft similarly in non immune-suppressed STZ-diabetic rhesus macaques (Rogers et al. 2007 Xenotransplantation 14, 591-602). Exogenous insulin requirements were shown to be reduced in transplanted macaques and porcine, but no primate insulin circulated following an intravenous glucose load. However, primates continued to require exogenous insulin to maintain euglycemia even after multiple transplantation surgeries (Rogers et al. 2007 Xenotransplantation 14, 591-602).